**4. Composition of an atherosclerotic plaque**

**2. Atherosclerotic plaque morphology**

86 Carotid Artery Disease - From Bench to Bedside and Beyond

characteristics and the composition of the atherosclerotic lesion.

further neurological events. [13]

**3. Plaque surface characteristics**

 

rhage.

[14-16]

Atherosclerotic plaques are not static lesions; they undergo dynamic changes in their size and morphological characteristics. These changes manifest themselves as changes in plaque volume and consistency, otherwise known as *plaque progression* and *regression*. These, together with adaptive responses of the arterial wall, determine the degree of stenosis in the diseased artery. [10-12] This degree of stenosis is the measurable clinical finding which, together with timing and nature of symptoms and co-morbidities, correlates with the risk of developing

Over the last 20 years a lot has been learned about the morphological characteristics of an atherosclerotic plaque responsible for plaque progression and instability. [10-12] Morpholog‐ ical characteristics of atherosclerotic plaques can be discussed in the context of plaque surface

Julian *et al* in 1963 were the first to discuss the issue of carotid plaque ulceration. They reported 17 cases of macroscopic plaque ulceration with thrombosis in the ulcer crater and suggested this as a source for embolisation. [12] Ulceration has been described as an observable disruption

There has been conflicting evidence regarding the significance of plaque ulceration in the evolution of symptomatic disease. In a large study, Imparato *et al* did not find any significant difference in the incidence of ulceration between 

**Figure-1: A carotid endarterectomy specimen containing a large ulcer which is** 

**Figure 1.** A carotid endarterectomy specimen containing a large ulcer which is associated with intra-plaque haemor‐

There has been conflicting evidence regarding the significance of plaque ulceration in the evolution of symptomatic disease. In a large study, Imparato *et al* did not find any significant difference in the incidence of ulceration between symptomatic and asymptomatic groups.

of intima exposing the adjacent atheromatous plaque or media [13] (figure 1).

symptomatic and asymptomatic groups.14‐16

**associated with intra-plaque haemorrhage.**

The raised lesion or fibro-lipid plaque is the archetypal lesion of atherosclerosis and compli‐ cations of this lesion (fissure and ulceration) form the basis of the vast majority of cases of occlusive arterial disease. All atherosclerotic plaques share two basic morphological compo‐ nents:

*Fibrous cap:* a thick layer of fibrous connective tissue, which is significantly thicker and much less cellular than the normal intima and contains lipid-filled macrophages, collagen and smooth muscle cells;

*Atheroma:* A necrotic mass of lipid that forms the core of the lesion. Loss of continuity of the endothelium is the main step in the progression of a plaque and increases the permeability of the intima to lipoproteins, permits platelet-vessel wall interaction and release of growth factors leading to formation of thrombus on the vessel wall.

Leahy demonstrated that various elements of the plaque are available as potential emboli. [20] This includes the fibrous cap overlying complex plaques, the contents that include cholesterol crystals, the breakdown products of intra-plaque haemorrhage, and fibrous or cartilaginous material as well as calcified tissue. Hollenhorst showed the presence of cholesterol emboli in the retinal artery of patients suffering from amaurosis fugax, in the form of bright plaques that were seen in the extra-cranial carotid vessels. [21] Bock *et al* reported that soft plaques (lipid laden and haemorrhagic plaque) behave in an unstable way and tend to ulcerate, whilst fibrous or calcified plaques behave differently. [22]

Based on the natural history and pathological changes within the plaque the American Heart Association (AHA) has classified atherosclerotic lesions [23] (table 1). This classification that has been modified by Virmani and Naghavi *et al* divides the atheromatous lesions into nonatherosclerotic intimal lesions and progressive atherosclerotic plaques. [24, 25] The classifica‐ tion, although not particularly directed at the carotid atherosclerotic lesions, is however applicable when classifying carotid plaques. Progressive atherosclerotic plaques (AHA plaque types V and VI) are relevant in the setting of clinically significant carotid disease (figure-2).

**5. The concept of unstable atherosclerotic plaque**

nary artery atherosclerosis. [31-34]

ruptures or remains contained by the fibrous cap.

**6. Angiogenesis in carotid atherosclerotic lesions**

The concept that a sub-group of atherosclerotic plaques are prone to embolisation or thrombosis is not new. As early as 1926, Benson postulated that coronary thrombosis results from disruption of intima that exposes lipids to flowing blood. [26] Constantinides was the first to establish conclusively that plaque rupture was the immediate cause of coronary thrombosis. [27] In a series of subsequent studies Davies *et al* established the importance of plaque fissuring, ulceration and subsequent thrombosis in the development of acute coronary syndromes. [28-30] Further clinical and angiographic work has led to progres‐ sion of this concept and introduction of thrombolytic therapy in the treatment of coro‐

Carotid Plaque Morphology: Plaque Instability and Correlation with Development of Ischaemic Neurological Events

http://dx.doi.org/10.5772/57254

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Atherosclerotic plaques that are prone to rupture are known to have certain cellular, molecular and structural features. Notably these include an intense inflammatory process within the plaque, angiogenesis, and intra-plaque haemorrhage with gradual thinning of the fibrous cap, subsequent loss of plaque cap integrity and ulceration. [35] Burke *et al* defined a vulnerable plaque in the coronary arteries as a lesion with a cap thickness of less than 65 µM [36]. Gertz *et al* noted that the lipid cores were much larger in areas of atherosclerotic plaque disruption than in lesions with intact surfaces. [37-38] Inflammatory activity within the plaque is associ‐

The evolution of atheroma is modulated by innate and adaptive immune responses which are recognized histologically as presence of an inflammatory infiltrate within the lesion [40]. These processes are responsible for replication and phenotypic change within the smooth muscle cell from contractile to secretory which results in formation of plaque cap and lesion growth. Intimal endothelial cell activation results in recruitment of macrophages and lymphocytes (predominantly CD4 positive T-cells) into evolving lesion. [40] Activation of Th-1 T-cells is known to initiate a potent inflammatory cascade which in turn leads to plaque instability [41]. Inflammatory cell infiltrate is a marker for plaque vulnerability. [42-47] Several factors such as oxidized lipoproteins, infectious agents or auto-antigens *(heat shock protein)* have been considered as the putative cause of the chronic inflammatory reaction in an atherosclerotic plaque. [40] This in turn results in weakening of the connective tissue framework of the plaque. [48, 49] Smooth muscles may help to counteract some of these effects by producing matrix protein, collagen and inhibitors of matrix degrading enzymes known as metalloproteinases. [50, 51] The net result of these two processes is thought to define whether or not the plaque

Normal human intima is devoid of blood vessels, [52] however newly formed blood vessels are often seen within atherosclerotic plaques [53-56] (figure-3). The presence and density of these new blood vessels in carotid atherosclerotic lesions has been associated with the histological features of plaque instability and intra-plaque haemorrhage as well as the

ated with plaque ulceration and has a role in pathogenesis of intimal damage. [39]


**Table 1.** American Heart Association has classification of atherosclerotic lesions [23] (*Circulation* 1995;92: 1355-74)

**Figure 2.** American Heart Association Type VI (Complicated atherosclerotic lesion) obtained from a carotid endarter‐ ectomy specimen. (*Br J Surg.* 2001;88:945–950.)
